P635: AN UPDATE OF SAFETY AND EFFICACY RESULTS FROM PHASE 1 STUDY OF LP-108, A NOVEL AND SELECTIVE BCL-2 INHIBITOR, IN PATIENTS WITH RELAPSED OR REFRACTORY B-CELL NON-HODGKIN LYMPHOMAS
Authors: Wei Xu, Ru Feng, LI Wang, Huayuan Zhu, Keshu Zhou, Xiaorui Fu, Hongmei Jing, Yuqin Song, Junyuan Qi, Guohui Cui, Fei LI, Shaoyuan Wang, Hui Zhou, Wenbin Qian, Qingqing Cai, Xielan Zhao, Xutao Guo, Xiaolei Wei, Ningjing Lin, Zhongyuan Xu, Zheng Wang, Xiang Xiao, Jiale Dong, Yejiang Lou, Yue Shen, Yi Chen, Yu Chen, Fenlai Tan, Stephen Anthony, Jianyong LI
Journal: HemaSphere (2023)

Background: The effectiveness of BCL-2 inhibition in hematologic malignancies has been demonstrated by venetoclax, a globally approved BCL-2 inhibitor that requires weekly dose ramp-up to mitigate the risk of tumor lysis syndrome (TLS) and its efficacy in Chinese patients with non-Hodgkin lymphomas (NHL) is obscure. LP-108 is a novel, highly potent, orally bioavailable, and selective BCL-2 inhibitor that has shown favorable pharmacokinetic and safety profiles and preliminary antitumor activity under daily dose ramp-up scheme in patients with relapsed or refractory (R/R) B-cell NHL at tested doses up to 600 mg (EHA 2022. Abstract P684). Aims: We present updated safety and efficacy results from the ongoing phase 1 study of LP-108 in Chinese patients with R/R B-cell NHL, including patients who had received prior Bruton’s tyrosine kinase inhibitor (BTKi) treatments (NCT04356846). Methods: Adult R/R B-cell NHL patients are treated with LP-108 at doses ranging from 20 mg to 1000 mg per day in dose-escalation phase to evaluate dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), and further expanded at 3 dose cohorts (200 mg, 400 mg or 600 mg), with 8 to 12 patients in each cohort, to determine recommended phase 2 dose. A daily ramp-up scheme was used before reaching the target dose (28 days per cycle). Results: As of Dec 12, 2022, 49 patients were enrolled and evaluable for safety. Diagnosis includes mantle cell lymphoma (MCL, n = 20), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, n = 19) or other B-cell NHL (n = 10). Patients had a median age of 64 years (range, 39-84) and received a median of 2 prior lines of therapies (range, 1-7), of which 28 (57.1%) patients were previously exposed to BTKi. No DLT has been observed up to 800 mg/day, thus MTD has not been reached. With a median duration of treatment (DOT) of 3.8 cycles (range, 0.2-27.4), treatment-related adverse events (TRAEs) of any grade occurred in ≥ 15% of patients were neutropenia (46.9%), leukopenia (30.6%), hyperuricemia (28.6%), hyperbilirubinemia (24.5%), hyperphosphatemia (24.5%), thrombocytopenia (24.5%), anemia (20.4%), AST elevation (18.4%), and hypocalcemia (16.3%), most of which were Grade 1 or 2. Grade 3 or 4 TRAEs (≥ 5%) were hematological toxicities including neutropenia (30.6%), anemia (12.2%), thrombocytopenia (12.2%), and leukopenia (10.2%), which were manageable. Serious TRAEs occurred in 8 (16.3%) patients, including neutropenia (3 [6.1%]), rash, anemia, laboratory TLS, hyperphosphatemia, asymptomatic pneumonia, upper respiratory tract infection and lung infection (1 [2%] each). One patient (2%) at 400 mg/day experienced dose reduction due to Grade 4 neutropenia. No patient discontinued treatment due to toxicity, and no clinical TLS or treatment-related death was observed, even with the rapid dose ramp-up. At doses ≥ 200 mg/day, 21 of 39 (overall response rate (ORR), 53.8%) efficacy evaluable patients achieved objective response. For R/R CLL/SLL, with a median DOT of 6.4 (range, 0.4-18.7) cycles, the ORR was 75% (12/16), including 3 patients achieving CR/CRi (18.7%). Among 6 CLL/SLL patients who had prior BTKi exposure, the ORR was 66.7% (4/6). For MCL (5 patients were with pleomorphic or blastoid variant), follicular Lymphoma (FL), and marginal zone lymphoma (MZL), the ORR was 40% (6/15), 100% (2/2) and 100% (1/1), respectively. Summary/Conclusion: LP-108 was well tolerated up to 800 mg/day with daily dose ramp-up schedule and showed encouraging antitumor activity in multiple types of B-cell NHL, even in those who had prior BTKi exposure.Keywords: BCL2, Phase I, Non-Hodgkin’s lymphoma, Chronic lymphocytic leukemia